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Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease
Sebastian Günther, Patrick Y.A. Reinke, Dominik Oberthuer, Oleksandr Yefanov, Helen Ginn, Susanne Meier, Thomas J. Lane, Kristina Lorenzen, Luca Gelisio, Wolfgang Brehm, Illona Dunkel, Martin Domaracky, Sofiane Saouane, Julia Lieske, Christiane Ehrt, Faisal Koua, Alexandra Tolstikova, Thomas A. White, Michael Groessler, Holger Fleckenstein, Fabian Trost, Marina Galchenkova, Yaroslav Gevorkov, Chufeng Li, Salah Awel, Ariana Peck, Lourdu P. Xavier, Miriam Barthelmess, Frank Schlünzen, Nadine Werner, Hina Andaleeb, Najeeb Ullah, Sven Falke, Bruno Alves Franca, Martin Schwinzer, Hévila Brognaro, Brandon Seychell, Henry Gieseler, Diogo Melo, Jo J. Zaitsev-Doyle, Brenna Norton-Baker, Juraj Knoska, Gisel Esperanza, Aida Rahmani Mashhour, Filip Guicking, Vincent Hennicke, Pontus Fischer, Cromarte Rogers, Diana C.F. Monteiro, Johanna Hakanpää, Jan Meyer, Heshmat Noei, Phil Gribbon, Bernhard Ellinger, Maria Kuzikov, Markus Wolf, Linlin Zhang, Xinyuanyuan Sun, Jonathan Pletzer-Zelgert, Jan Wollenhaupt, Christian Feiler, Manfred Weiss, Eike-Christian Schulz, Pedram Mehrabi, Christina Schmidt, Robin Schubert, Huijong Han, Boris Krichel, Yaiza Fernández-García, Beatriz Escudero-Pérez, Stephan Günther, Dusan Turk, Charlotte Uetrecht, Tobias Beck, Henning Tidow, Ashwin Chari, Andrea Zaliani, Matthias Rarey, Russell Cox, Rolf Hilgenfeld, Henry N. Chapman, Arwen R. Pearson, Christian Betzel, and Alke Meents(preprint, 2020)
Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.
Tags: corona, covid, European XFEL, XBI
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